Cell matrix and cell-cell interactions are important physiological determinants of cell growth, survival and transformation. Cell adhesion to extra cellular matrix (ECM) via integrins also crucially influences the organization of cytoskeleton. Ligand binding to integrins leads to integrin clustering and recruitment of actin filaments and signaling proteins to the cytoplasmic domain of integrin (Hynes, R. O., 2002. Integrins: Bidirectional, allosteric signaling machines. Cell. 110, 673-687). These complexes provide outside in signaling to regulate diverse cellular functions balancing survival and death pathways in both normal and tumorigenic cells (Assoian R K, Schwartz M A. 2001. Coordinate signaling by integrins and receptor tyrosine kinases in the regulation of G1 phase cell-cycle progression. Curr Opin Genet Dev. 11(1): 48-53). Most of the adhesion dependent cells undergo apoptosis after deprivation of substratum. Integrin ligation can rescue these cells, which demonstrate that integrins are involved in stimulating apoptosis resistant mechanisms and allow the ceils to undergo transformation (Rajeswari, J and Pande, G. 2002. The significance of α5β1 integrin dependent and independent cytoskeleton organization in cell transformation and survival. Cell Biol. Int. 26, 1043-1055). Integrins also provide signals to detach from primary tumors, to invade and colonize at secondary sites during metastasis (Lodish, H., Berk, A., Zipursky, S. L., Matsudaira, P., Baltimore, D., and Darnell, J. 2002. Molecular Cell Biology 4th ed., W.H. Freeman and Company, New York, pp. 751-792, 817-822, 970-988, 1056-1082 and Seiki, M., Koshikawa, N., Yana, I., 2003. Role of pericellular proteolysis by membrane-type1 matrix metalloproteinase in cancer invasion and angiogenesis. Cancer and Metastasis Reviews. 22 (2), 129-143, Ledezma, 2004) and angiogenesis (Stupack D G, Cheresh D A. Integrins and angiogenesis. 2004 Curr Top Dev Biol. 64, 207-38.). In contrast, some cancerous cells die rather than to colonize at distant sites (Rust et. al., 2002). Hence changes in the integrin expression profiles may dramatically influence the progression of malignant tumors by inducing various signaling molecules such as Jun kinases (JNKs), p38-kinase, Bad and various caspases.
Several recent studies have shown the effectiveness of integrins as indicators of diseases such as cancer and angiogenesis. Both up regulation and down regulation of integrin expression could serve as effective markers in cancer detection. For e.g. down regulation of α6 and β4 may contribute to higher tumorigenesis in prostate cancer cells (Bonaccorsi L, Carloni V, Muratori M, Salvadori A, Giannini A, Carini M, Serio M, Forti G, Baldi E. 2000 Endocrinology. 141(9), 3172-82). Androgen receptor expression in prostate carcinoma cells suppresses alpha6beta4 integrin-mediated invasive phenotype. The clinical correlations of patient biopsies to integrin expression are recapitulated to some degree in rodent and in vitro analyses. For example, a study of rat hepatocarcinogenesis showed that integrins α1 and α5 were up-regulated in metastases of the lung and diaphragm, while integrins α1, α2, α3, and α5 were decreased in the primary carcinoma and preneoplastic nodules (Rust W L, Carper R S and Plopper G E. 2002. The promise of integrins as effective targets for anticancer agents. J Biomed Biotechnol. 2002; 124-130).
The regulatory mechanisms of cell survival and apoptosis are very complex in nature, implicating numerous players and signaling pathways not only in the decision-making process of surviving (or dying), but as well as in the execution of apoptosis itself. The same complex nature applies with regards to anoikis, a form of apoptosis that is largely regulated by integrin-mediated cell-extracellular matrix interactions.
Majority of cancer-related deaths are associated with metastasis. The metastatic cascade is a complex process consisting of a number of important steps that include loss of tissue architecture, local invasion, invasion into blood and lymph vessels, extravasation, establishment of the secondary foci and angiogenesis. Invasion of the extracellular matrix and metastatic spread of cancer to other tissues is also likely to reflect the ability of tumour cells to digest their surrounding matrix scaffold through secretion of matrix-degrading enzymes such as matrix metalloproteinases (MMPs). Invasion of the extracellular matrix and metastatic spread of colon cancer is also likely to reflect the ability of tumour cells to digest their surrounding matrix scaffold through secretion of matrix-degrading enzymes such as matrix metalloproteinases (MMPs). The mechanisms whereby human colon cancer cells escape the constraints on growth imposed on normal cells by cell crowding and dense pericellular matrices isomclear. However, the mechanisms whereby tumorigenic cells escape the constraints on growth imposed on normal cells by cell crowding and dense pericellular matrices is unclear (A method of modulating integrin mediated cellular activity and agents useful for same. 2001. WO/2001/000677).